rs1554058577

Positions:

• chr5-13810077-AGTCGAAGGCGGT-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PM4 PP3 PP5_Moderate

The NM_001369.3(DNAH5):​c.7579_7590delACCGCCTTCGAC​(p.Thr2527_Asp2530del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000714 in 1,400,398 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: DNAH5 NM_001369.3 conservative_inframe_deletion
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 9.05

Genes affected

DNAH5 (HGNC:2950): (dynein axonemal heavy chain 5) This gene encodes a dynein protein, which is part of a microtubule-associated motor protein complex consisting of heavy, light, and intermediate chains. This protein is an axonemal heavy chain dynein. It functions as a force-generating protein with ATPase activity, whereby the release of ADP is thought to produce the force-producing power stroke. Mutations in this gene cause primary ciliary dyskinesia type 3, as well as Kartagener syndrome, which are both diseases due to ciliary defects. [provided by RefSeq, Oct 2009]

DNAH5 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_001369.3.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 5-13810077-AGTCGAAGGCGGT-A is Pathogenic according to our data. Variant chr5-13810077-AGTCGAAGGCGGT-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 454804.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH5	NM_001369.3	c.7579_7590delACCGCCTTCGAC	p.Thr2527_Asp2530del	conservative_inframe_deletion	45/79	ENST00000265104.5	NP_001360.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH5	ENST00000265104.5	c.7579_7590delACCGCCTTCGAC	p.Thr2527_Asp2530del	conservative_inframe_deletion	45/79	1	NM_001369.3	ENSP00000265104.4
DNAH5	ENST00000681290.1	c.7534_7545delACCGCCTTCGAC	p.Thr2512_Asp2515del	conservative_inframe_deletion	45/79			ENSP00000505288.1
DNAH5	ENST00000512443.1	n.435_446delACCGCCTTCGAC		non_coding_transcript_exon_variant	1/3	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.14e-7 AC: 1 AN: 1400398 Hom.: 0 AF XY: 0.00000145 AC XY: 1 AN XY: 691086

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000277

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary ciliary dyskinesia Pathogenic:1 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 29, 2022	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. ClinVar contains an entry for this variant (Variation ID: 454804). This variant has been observed in individual(s) with clinical features of DNAH5-related conditions (PMID: 32502479; Invitae). This variant is not present in population databases (gnomAD no frequency). This variant, c.7579_7590del, results in the deletion of 4 amino acid(s) of the DNAH5 protein (p.Thr2527_Asp2530del), but otherwise preserves the integrity of the reading frame. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Jun 11, 2021	- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1554058577; hg19: chr5-13810186;